PET Imaging of Brain Tumor Angiogenesis and Antiangiogenic Treatment

我们的长期目标是开发用于脑肿瘤成像的PET成像技术，以识别在脑肿瘤生长和扩散过程中改变的分子结构和受体，并帮助预测自然史和对治疗的反应。本提案的目的是通过PET和MRI对脑肿瘤血管生成和抗血管生成治疗效果进行成像。脑肿瘤是血管生成依赖性的。抗血管生成疗法，无论是阻断肿瘤血管生成相关蛋白的表达或直接阻止内皮细胞迁移和诱导凋亡，已被证明是有效的脑肿瘤。我们先前已经开发了一系列基于α v-整联蛋白拮抗作用的用于脑肿瘤模型的PET成像的环状RGB肽放射性示踪剂。肿瘤靶向疗效和药代动力学 整合素特异性PET示踪剂依赖于其受体结合亲和力、亲水性和分子大小等。本项目将扩展我们的研究，旨在：（1）优化整合素特异性PET示踪剂的临床应用;（2）将α-v整合素表达水平与肿瘤大小相关联，（肿瘤细胞和肿瘤脉管系统两者）示踪剂摄取;和（3）评价用PET/MRI组合的抗整联蛋白脑肿瘤治疗。总的来说，该提议将以新颖且独特的方式促进我们对与α-v整联蛋白表达相关的脑肿瘤血管生成的理解，并允许基于α-整联蛋白靶向PET成像直接评估抗血管生成治疗功效。这将导致PET探针的直接临床转化，并且还允许对其他肿瘤的血管生成进行成像（例如，研究项目2中研究的淋巴瘤）。此外，它应该有助于显示成像的作用，以监测 抗癌疗法，以加速新一代抗血管生成剂的测试。

Our long-range objectives are to develop PET imaging techniques for brain tumor imaging in order to identify molecular structures and receptors that are altered during brain tumor growth and spread and to help predict the natural history and response to therapy. The objective in this proposal is to image brain tumor angiogenesis and anti-angiogenic therapy efficacy by means of PET and MRI. Brain tumors are angiogenesis dependent. Anti-angiogenic therapies that either block expression of tumor angiogenesis related proteins or directly prevent endothelial cells from migration and induce apoptosis, have been proven effective in brain tumors. We have previously developed a series of cyclic RGB peptide radiotracers for PET imaging of brain tumor models based upon av-integrin antagonism. The tumor targeting efficacy and pharmacokinetics of the tracers are highly dependent on their receptor binding affinity, hydrophilicity, and molecular size, etc. This project will expand our investigations with aim to: (1) optimize the integrin specific PET tracers for clinical applicability; (2) correlate alpha-v integrin expression level with the magnitude of tumor (both tumor cells and rumor vasculature) tracer uptake; and (3) evaluate anti-integrin brain tumor treatment with a PET/MRI combination. Overall, this proposal will foster in a novel and unique way our understanding of brain tumor angiogenesis in relationship to alpha-v integrin expression and allow for direct assessment of anti-angiogenic treatment efficacy based upon alpha-integrin targeted PET imaging. This should lead to direct clinical translation of the PET probes validated and also allow imaging of angiogensis for other tumors (e.g., for lymphomas studied in Research Project 2). Furthermore it should help show the role of imaging to monitor anti-cancer therapies for acceleration of testing of new generation of anti-angiogenesis agents.